Peter C. DeMuth

Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination

Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release. To this end, a microneedle materials platform is demonstrated for rapid implantation of controlled-release polymer depots into the cutaneous tissue. Arrays of microneedles composed of drug-loaded poly(lactide-co-glycolide) (PLGA) microparticles or solid PLGA tips are prepared with a supporting and rapidly water-soluble poly(acrylic acid) (PAA) matrix. Upon application of microneedle patches to the skin of mice, the microneedles perforate the stratum corneum and epidermis. Penetration of the outer skin layers is followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which are retained following patch removal. These polymer depots remain in the skin for weeks following application and sustain the release of encapsulated cargos for systemic delivery. To show the utility of this approach the ability of these composite microneedle arrays to deliver a subunit vaccine formulation is demonstrated. In comparison to traditional needle-based vaccination, microneedle delivery gives improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery. However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts.

Implantable Silk Composite Microneedles for Programmable Vaccine Release Kinetics and Enhanced Immunogenicity in Transcutaneous Immunization

Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local inflammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profiles present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1-2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in >10-fold increases in antigen-specific T-cell and humoral immune responses relative to traditional parenteral needle-based immunization.

Vaccine delivery with microneedle skin patches in nonhuman primates

Peter C. DeMuth1,2, Adrienne V. Li1, Peter Abbink3, Jinyan Liu3, Hualin Li3, Kelly A. Stanley3, Kaitlin M. Smith3, Christy L. Lavine3, Michael S. Seaman3, Joshua A. Kramer4, Andrew D. Miller4, Wuhbet Abraham1,2,5, Heikyung Suh1,2,5, Jamal Elkhader1, Paula T. Hammond2,6,7, Dan H. Barouch3,8, and Darrell J. Irvine1,2,7,8,9 1Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, 02139 USA